For several years after the isolation of vitamin B12 as cyanocobalamin in 1948, it was assumed that cyanocobalamin and possibly hydroxocobalamin, its photolytic breakdown product, occurred in man. Since then it has been recognized that cyanocobalamin is an artifact of the isolation of vitamin B2 and that hydroxocobalamin and the two coenzyme forms, methylcobalamin and adenosylcobalamin, are the naturally occurring forms of the vitamin.
The structure of these various forms is shown in FIG. 1, wherein X is CN, OH, CH3 or adenosyl, respectively. Hereinafter, the term cobalamin will be used to refer to all of the molecule except the X group. The fundamental ring system without cobalt (Co) or side chains is called corrin and the octadehydrocorrin is called corrole. FIG. 1 is adapted from The Merck Index, Merck & Co. (11th ed. 1989), wherein X is above the plane defined by the corrin ring and nucleotide is below the plane of the ring. The corrin ring has attached six amidoalkyl (H2NC(O)Alk) substituents, at the 2, 3, 7, 8, 13, and 18 positions, which can be designated a-e and g, respectively. See D. L. Anton et al., J. Amer. Chem. Soc., 102, 2215 (1980). The 2, 3, 7, 8, and 13 positions are shown in FIG. 1 as positions a-e, respectively.
Cells undergoing rapid proliferation have been shown to have increased uptake of thymidine and methionine. (See, for example, M. E. van Eukeren et al., Acta Oncologica, 31, 539 (1992); K. Kobota et al., J. Nucl. Med., 32, 2118 (1991) and K Higashi et al., J. Nucl. Med. 34, 773 (1993)). Since methylcobalamin is directly involved with methionine synthesis and indirectly involved in the synthesis of thymidylate and DNA, it is not surprising that methylcobalamin as well as Cobalt-57-cyanocobalamin have also been shown to have increased uptake in rapidly dividing tissue (for example, see, B. A. Cooper et al., Nature, 191, 393 (1961); H. Flodh, Acta Radiol. Suppl., 284. 55 (1968); L. Bloomquist et al., Experientia, 25, 294 (1969)). Additionally, up-regulation in the number of transcobalamin II receptors has been demonstrated in several malignant cell lines during their accelerated thymidine incorporation and DNA synthesis (see, J. Lindemans et al., Exp. Cell Res., 184, 449 (1989); T. Amagasaki et al., Blood, 26, 138 (1990) and J. A. Begly et al., J. Cell Physiol, 156, 43 (1993).
U.S Pat. No. 5,739,313 discloses cobalamin analogs which comprise a compound of formula I, a linking group, a chelating group and a detectable radionuclide or a detectable paramagnetic ion. The compounds localize in tumor cells following administration and are useful for imaging tumors. Although the compounds are useful as tumor imaging agents, the specific compounds prepared therein comprise one detectable radionuclide or one detectable paramagnetic ion and thus have a limited detection capability. As such there is a need for additional imaging agents. Particular agents will have a relatively high bioavailability, a relatively low toxicity or are detectable at a relatively low concentration. In addition, there is a need for additional therapeutic agents.